Choreography of Eukaryotic DNA Replication

真核 DNA 复制的编排

• 批准号: 9900022
• 负责人: BONITA J BREWER
• 金额: $ 55.17万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900022
• 关键词: Address; Animal Model; Autoimmune Diseases; Basal Cell Nevus Syndrome; Biological Models; Categories; Cell Cycle; Cells; Chromosome Structures; Chromosome abnormality; Chromosomes; Copy Number Polymorphism; DNA biosynthesis; DNA replication fork; Defect; Disease; Eukaryota; Fire - disasters; Genes; Genetic; Genetic Diseases; Genomic Instability; Genomics; Goals; Human; Lead; Licensing; Life; Link; Lupus Erythematosus; Malignant Neoplasms; Molecular; Monitor; Mus; Mutation; Point Mutation; Process; Regulation; Replication Origin; S Phase; Site; System; Time; Work; Yeasts; chromosome replication; developmental disease; event cycle; genome integrity; helicase; malignant breast neoplasm

PROJECT SUMMARY DNA replication is undeniably important for life and as a consequence, cells have evolved mechanisms to monitor replication fidelity and to coordinate completion of replication with other cell cycle events. The goal of this project is to understand how cells choreograph the duplication of their chromosomes, and how defects in DNA replication may contribute to some disorders in humans. Chromosome replication in eukaryotes is a process that involves the regulation of multiple initiation sites (origins) per chromosome that vary in their initiation timing (not all origins fire at the same time in S phase) and efficiency (not all origins fire in every cell cycle). Understanding how origin use is regulated is therefore critical for understanding how genome integrity is maintained. This notion is underscored by genetic disorders with links to replication defects: 1) Meier-Gorlin Syndrome with its point mutations in genes essential for origin licensing; 2) the mouse chaos3 mutation in a gene encoding part of the replicative helicase that is associated with breast cancer in mice; and 3) forms of replication fork errors that potentially contribute to human segmental copy number variants and autoimmune disorders such as lupus erythematosus. Yeast is an ideal model organism for studying DNA replication because of its small chromosomes, well defined origin sequences, ease of altering chromosome structure, and exceptional systems for genetic and genomic analysis. This project will address outstanding questions regarding why the choreography of chromosome replication is so important in eukaryotes: why do origins initiate replication at different times, what distinguishes origins in different temporal categories, what is the molecular basis for inefficient origins, and how do defects in replication origin firing and/or fork progression lead to genome instability and consequent disease states?

项目概要 DNA 复制对于生命来说无疑是重要的，因此，细胞已经进化出机制来 监测复制保真度并协调复制的完成与其他细胞周期事件。这 该项目的目标是了解细胞如何编排染色体的复制，以及如何 DNA 复制缺陷可能导致人类某些疾病。染色体复制在 真核生物是一个涉及每条染色体多个起始位点（起源）调节的过程 其启动时间（并非所有源在 S 阶段同时点火）和效率（并非所有源）各不相同 每个细胞周期中都起源火）。因此，了解原产地使用的监管方式对于 了解如何保持基因组完整性。遗传性疾病强调了这一概念 与复制缺陷的联系：1) 迈尔戈林综合征及其起源必需基因的点突变 许可； 2) 编码相关复制解旋酶部分的基因中的小鼠 Chaos3 突变 小鼠患有乳腺癌； 3）复制叉错误的形式可能会导致人类 节段拷贝数变异和自身免疫性疾病，如红斑狼疮。酵母是一种理想的 由于其染色体小、起源明确，因此成为研究 DNA 复制的模型生物 序列、易于改变染色体结构以及遗传和基因组的特殊系统 分析。该项目将解决有关为什么染色体编排的悬而未决的问题 复制在真核生物中如此重要：为什么起源在不同的时间启动复制，什么 区分不同时间类别中的起源，低效起源的分子基础是什么，以及 复制起点激发和/或分叉进展的缺陷如何导致基因组不稳定以及 随之而来的疾病状态？